Candesartan Cilexetil and precursor compound preparation method thereof
The technology of a precursor compound, candesartan cilexetil, is applied in the direction of organic chemistry, which can solve the problems of unsatisfactory yield, difficult preparation, complex structure, etc.
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Embodiment 1
[0026] 2-Ethoxy-1-[[2'-(trityltetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole- Preparation of 1-(cyclohexyloxycarbonyloxy)ethyl 7-carboxylate (III)
[0027] Put 80 parts of a mixed solvent composed of DME / THF at 1 / 1 (volume) into the reactor, blow in nitrogen to remove the air in the system, and then put in 1 part of triphenylphosphine (Ph3P) and 20.2 parts of Pd(OAc) , stirred at room temperature for 30 minutes, then added 10 parts of 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid (II), and continued stirring at room temperature for 10 minutes. Join K in sequence 2 CO 3 6 parts of fine powder, 2-ethoxy-1-(4'-bromophenyl)methyl-1H-benzimidazole 7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 12 parts of ester (I), heated to about 75°C and refluxed for 15 hours (monitored by TLC: Hex / EtOAc 2:1).
[0028] Cool to normal temperature, filter with suction, and the filtrate can be distilled off under reduced pressure to remove most of the solvent. To the re...
Embodiment 2
[0030] 2-Ethoxy-1-[[2'-(trityltetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-benzimidazole- Preparation of 1-(cyclohexyloxycarbonyloxy)ethyl 7-carboxylate (III)
[0031] Put 80 parts of dioxane into the reactor, pass through nitrogen to remove the air in the system, add 0.2 parts of triphenylphosphine (Ph3P) and 40.5 parts of Pb[Ph3] in sequence, stir at room temperature for 30 minutes, and then add 2- 10 parts of ethyl (1-trityl-1H-tetrazol-5-yl)phenylboronate (II) were stirred at room temperature for 10 minutes. Add 6 parts of K2CO3 fine powder, 2-ethoxy-1-(4'-bromophenyl)methyl-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl] 12 parts of oxy]ethyl ester (I), warmed up to 90°C and kept the reaction for 6 hours (monitored by TLC: Hex / EtOAc=2 / 1).
[0032] Cool to normal temperature, filter with suction, and the filtrate can be distilled off under reduced pressure to remove most of the solvent. Add 80ml of toluene and 80ml of water to the residue, let stand to ...
Embodiment 3
[0034] The preparation of candesartan cilexetil (IV)
[0035] The 2-ethoxy-1-[[2′-(trityltetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]- 10 g of 1-(cyclohexyloxycarbonyloxy) ethyl 1H-benzimidazole-7-carboxylate (III), dissolved in 80 ml of acetone, adjusted to pH 2 with 5% hydrochloric acid at room temperature, and stirred for 5-10 hours , monitor the progress of the reaction by means of thin-layer chromatography (thin-layer chromatography monitoring: chloroform: petroleum ether: methanol = 4: 3: 1) or high performance liquid chromatography.
[0036] Then, 5% NaOH aqueous solution was slowly added dropwise to the reactant to neutrality, most of the acetone was removed by distillation under reduced pressure, 50 ml of ethyl acetate was added, cooling and crystallization, continued stirring for 30 minutes and then filtering. After the filter cake was washed with an appropriate amount of glacial ethyl acetate, it was purified in DMF / water, or purified by silica gel column chromatogra...
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